Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

Kazdoba, Tatiana M.; Leach, Prescott T.; Yang, Mu; Silverman, Jill L.; Solomon, Marjorie; Crawley, Jacqueline N.

doi:10.1007/7854_2015_5003

Cited by 111 publications

(123 citation statements)

References 364 publications

(378 reference statements)

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“…Expanding knowledge about genetic mutations that cause neurodevelopmental disorders has prompted the generation of mouse models with the syntenic mutation, for use in understanding biological mechanisms, and as translational tools to develop therapeutics (Capecchi, 2005; Geyer, 2008; Lynch et al, 2008; Khwaja and Sahin, 2011; Das and Reeves, 2011; Huang et al, 2011; Crawley, 2012; Kleschevnikov et al, 2012; Baudry et al, 2012; Kas et al, 2014; Vorstman et al, 2014; Hatami and Chesselet, 2015; Kazdoba et al, 2016a,b; Belichenko et al, 2016; Gogliotti et al, 2016; Duffney et al, 2016). For neurodevelopmental disorders in which the primary symptom is intellectual impairment, the corresponding mouse model will ideally display robust and highly reproducible cognitive deficits.…”

Section: Introductionmentioning

confidence: 99%

Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

Leach

Crawley

2018

Genes Brain and Behavior

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Mutant mouse models of neurodevelopmental disorders with intellectual disabilities provide useful translational research tools, especially in cases where robust cognitive deficits are reproducibly detected. However, motor, sensory and/or health issues consequent to the mutation may introduce artifacts that preclude testing in some standard cognitive assays. Touchscreen learning and memory tasks in small operant chambers have the potential to circumvent these confounds. Here we use touchscreen visual discrimination learning to evaluate performance in the maternally derived Ube3a mouse model of Angelman syndrome, the Ts65Dn trisomy mouse model of Down syndrome, and the Mecp2 mouse model of Rett syndrome. Significant deficits in acquisition of a 2-choice visual discrimination task were detected in both Ube3a and Ts65Dn mice. Procedural control measures showed no genotype differences during pretraining phases or during acquisition. Mecp2 males did not survive long enough for touchscreen training, consistent with previous reports. Most Mecp2 females failed on pretraining criteria. Significant impairments on Morris water maze spatial learning were detected in both Ube3a and Ts65Dn, replicating previous findings. Abnormalities on rotarod in Ube3a, and on open field in Ts65Dn, replicating previous findings, may have contributed to the observed acquisition deficits and swim speed abnormalities during water maze performance. In contrast, these motor phenotypes do not appear to have affected touchscreen procedural abilities during pretraining or visual discrimination training. Our findings of slower touchscreen learning in 2 mouse models of neurodevelopmental disorders with intellectual disabilities indicate that operant tasks offer promising outcome measures for the preclinical discovery of effective pharmacological therapeutics.

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Section: Introductionmentioning

confidence: 99%

Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

Leach

Crawley

2018

Genes Brain and Behavior

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“…Mice are particularly advantageous for examining the genetic architecture of sociability because of their high levels and lifelong expression of affiliative behaviors . Outbred and unrelated‐inbred mouse strains show differences in affiliative and aggressive social behavior and mutant mice have been the focus of numerous candidate gene studies …”

Section: Introductionmentioning

confidence: 99%

Quantitative trait locus mapping and analysis of heritable variation in affiliative social behavior and co‐occurring traits

Knoll

Jiang

Levitt

2017

Genes Brain and Behavior

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Humans exhibit broad heterogeneity in affiliative social behavior. Twin and family studies show that individual differences in core dimensions of social behavior are heritable, yet there are knowledge gaps in understanding the underlying genetic and neurobiological mechanisms. Animal genetic reference panels (GRPs) provide a tractable strategy for examining the behavioral and genetic architecture of complex traits. Here, using males from 50 mouse strains from the BXD GRP, 4 domains of affiliative social behavior—social approach, social recognition, direct social interaction (DSI) (partner sniffing) and vocal communication—were examined in 2 widely used behavioral tasks—the 3‐chamber and DSI tasks. There was continuous and broad variation in social and nonsocial traits, with moderate to high heritability of social approach sniff preference (0.31), ultrasonic vocalization (USV) count (0.39), partner sniffing (0.51), locomotor activity (0.54‐0.66) and anxiety‐like behavior (0.36). Principal component analysis shows that variation in social and nonsocial traits are attributable to 5 independent factors. Genome‐wide mapping identified significant quantitative trait loci for USV count on chromosome (Chr) 18 and locomotor activity on Chr X, with suggestive loci and candidate quantitative trait genes identified for all traits with one notable exception—partner sniffing in the DSI task. The results show heritable variation in sociability, which is independent of variation in activity and anxiety‐like traits. In addition, a highly heritable and ethological domain of affiliative sociability—partner sniffing—appears highly polygenic. These findings establish a basis for identifying functional natural variants, leading to a new understanding typical and atypical sociability.

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“…The number of children suffered from ASD is increasing dramatically. As we know, the pathogenesis of ASD is complex and may be associated with genetic factor, immune, environment, education, diet, and so on 3. However, the etiology of ASD is unclear, and an objective diagnostic criteria and treatment options are still lacking.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin modulated brain-derived neurotrophic factor and B-cell lymphoma 2 to mitigate autism spectrum disorder in rats

Zhang¹,

Li²,

Ni³

2017

NDT

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The number of children suffered from autism spectrum disorder (ASD) is increasing dramatically. However, the etiology of ASD is not well known. This study employed mammalian target of rapamycin inhibitor rapamycin to explore its effect on ASD and provided new therapeutic strategies for ASD. ASD rat model was constructed and valproic acid (VPA) was injected intraperitoneally into rats on pregnancy day 12.5. Offspring from VPA group were divided into ASD group and ASD + rapamycin (ASD + RAPA) group. Compared with normal group, the frequency and duration of social behavior and straight times of ASD group were shortened, but the grooming times were extended. Meanwhile, in ASD group, the average escape latency and the frequency of crossing plates were decreased, the apoptotic index (AI) detected by TUNEL assay was increased, and the expression of brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) analyzed was decreased with great difference compared with normal group (P<0.01). However, rapamycin treatment in ASD rats mitigated the ASD-like social behavior, such as the frequencies of straight and grooming. Furthermore, rapamycin shortened the average escape latency, but increased the frequency of crossing plates of ASD rats. In hippocampus, rapamycin decreased the AI, but increased the levels of BDNF and Bcl-2 (P<0.01) of ASD rats. These findings revealed that rapamycin significantly mitigated the social behavior by enhancing the expression of BDNF and Bcl-2 to suppress the hippocampus apoptosis in VPA-induced ASD rats.

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Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

Cited by 111 publications

References 364 publications

Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities

Quantitative trait locus mapping and analysis of heritable variation in affiliative social behavior and co‐occurring traits

Rapamycin modulated brain-derived neurotrophic factor and B-cell lymphoma 2 to mitigate autism spectrum disorder in rats

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